WO2017203048A1 - Utilisation de l'inosine pour le traitement de la déficience en lymphocytes t régulateurs (t-reg) - Google Patents

Utilisation de l'inosine pour le traitement de la déficience en lymphocytes t régulateurs (t-reg) Download PDF

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Publication number
WO2017203048A1
WO2017203048A1 PCT/EP2017/062800 EP2017062800W WO2017203048A1 WO 2017203048 A1 WO2017203048 A1 WO 2017203048A1 EP 2017062800 W EP2017062800 W EP 2017062800W WO 2017203048 A1 WO2017203048 A1 WO 2017203048A1
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Prior art keywords
inosine
production
strain
treg
disease
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PCT/EP2017/062800
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English (en)
Inventor
Stefan Roos
Yuying Liu
Baokun HE
Jon Marc RHOADS
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Biogaia Ab
Board Of Regents Of The University Of Texas System
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Application filed by Biogaia Ab, Board Of Regents Of The University Of Texas System filed Critical Biogaia Ab
Priority to CN201780046556.6A priority Critical patent/CN110087656A/zh
Priority to US16/304,747 priority patent/US11602551B2/en
Priority to EP17728468.4A priority patent/EP3463385A1/fr
Publication of WO2017203048A1 publication Critical patent/WO2017203048A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants

Definitions

  • This invention relates to certain uses of inosine in the treatment of humans.
  • This invention further relates to a method for the selection of specific bacterial strains, including lactic acid bacterial strains, capable of stimulating inosine production and the use of such strains to deliver beneficial effects for a host organism.
  • Inosine is a nucleoside that is formed when hypoxanthine is attached to a ribose ring and is commonly found in tRNAs. Inosine is known to have potent immunomodulatory and neuroprotective effects and is available commercially as a dietary supplement. Inosine produces uric acid after ingestion and is suggested to be a natural antioxidant. Inosine has been studied in several clinical trials in, e.g. Parkinson's disease and multiple sclerosis. Probiotics are defined as microorganisms that provide health benefits when consumed. For example, The Food and Agricultural Organization of the United Nations define probiotics as "live microorganisms which when administered in adequate amounts confer a health benefit on the host".
  • Certain strains of lactic-acid producing bacteria such as Lactobacillus and Bifidobacteria are commonly used as probiotics in various types of foods, for example yoghurt. Growth and colonization of harmful microorganisms can be prevented by lactic acid producing bacteria through their own colonization on or inside the mammal, through formation of bio films, through competition of available nutrients and also the production of specific substances such as hydrogen peroxides, bacteriocines, or organic acids (including lactic acid and acetic acid) that lower the pH.
  • Some strains of for example lactic acid bacteria have also been shown to have effect in the treatment regimes of inflammatory disorders and also to have effects on the immune maturation and homeostasis of the host.
  • the regulatory T cells are a subpopulation of T cells which modulate the immune system, maintain tolerance to self-antigens, and abrogate autoimmune disease.
  • Tregs generally suppress or down regulate induction and proliferation of effector T cells.
  • Regulatory T cells come in many forms with the most well-understood being those that express CD4, CD25, and Foxp3 (CD4+CD25+ regulatory T cells).
  • CD4, CD25, and Foxp3 CD4+CD25+ regulatory T cells.
  • the present invention is based on the surprising finding that inosine alone can compensate for Treg deficiency or Treg dysfunction, when studying the scurfy mouse model, which is a model for immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX syndrome) due to a mutation of Foxp3.
  • IPEX syndrome immunodysregulation polyendocrinopathy enteropathy X-linked syndrome
  • This is an advantageous finding for therapy of various diseases that have some kind of Treg-dysfunction or even in cases where there is a lack of or reduced numbers of Treg-cells.
  • the present invention is further based on the surprising finding that certain strains of lactic acid bacteria, in particular strains of Lactobacillus reuteri, are capable of stimulating in vivo inosine production. Indeed, to the inventors' knowledge, probiotics have not before been reported to produce inosine or to stimulate inosine production in vivo.
  • the present invention thus also provides a new method of selecting specific bacterial strains, including strains of lactic acid bacteria, that are effective in stimulating or inducing inosine production in vivo.
  • the present invention provides inosine for use in the treatment of a disease associated with Treg deficiency or Treg dysfunction.
  • the present invention provides a method of treating a disease associated with Treg deficiency or Treg dysfunction in a subject, said method comprising the step of administrating an effective amount of inosine to said subject.
  • the present invention provides the use of inosine in the manufacture of a medicament or composition for use in the treatment of a disease associated with Treg deficiency or Treg dysfunction.
  • the inosine can be provided by administration of a bacterial strain.
  • inosine is provided by the administration of a bacterial strain, e.g. a lactic acid bacterial strain, that is capable of stimulating or inducing the production of inosine.
  • Figure 1 Experimental scheme, a, Scheme for Z. reuteri early treatment of SF mice (SFL), starting at 8 days of age (d8), daily, to dl25 for survival determination, b, L. reuteri: late treatment of SF mice (SFL), starting at dl5, daily, to d38 for survival determination, c, Inosine treatment of SF mice (SFI), starting on d8, given daily until dl25 for survival analysis.
  • SFL Scheme for Z. reuteri early treatment of SF mice (SFL), starting at 8 days of age (d8), daily, to dl25 for survival determination
  • b L. reuteri: late treatment of SF mice (SFL), starting at dl5, daily, to d38 for survival determination
  • c Inosine treatment of SF mice (SFI), starting on d8, given daily until dl25 for survival analysis.
  • SF mice autoimmunity in SF mice
  • b Representative H&E staining of liver and lung of WT, SF and SFL mice at d22.
  • d Levels of IFN- ⁇ and IL-4 in plasma, e, f, The proportion of IFN- ⁇ or IL-4-producing-CD4 + T cells in spleen (e) and mesenteric lymph nodes (f).
  • Error bars means ⁇ s.e.m. ** p ⁇ 0.01, *** p ⁇ 0.001.
  • Figure 5 L.
  • SF mice c
  • the scale bar indicates fold change of SF vs. WT or SFL vs. SF.
  • d Numbers of plasma metabolites affected, either up-regulated ( ⁇ ) or down-regulated (J,) (p ⁇ 0.05), by SF vs. WT or SFL vs. SF mice, e, Heat map showing the levels of 29 plasma metabolites that were significantly altered in SF mice with L. reuteri early treatment. Colors indicate fold change (SF vs. WT or SFL vs. SF). All changes indicated are p ⁇ 0.05 by two-way ANOVA with contrasts.
  • G green
  • LG light green
  • LR light red
  • R red.
  • Figure 8 Inosine suppresses TJJ1/TJJ2 differentiation and autoimmunity in SF mice.
  • the present invention provides inosine for use in the treatment of a disease associated with Treg deficiency or Treg dysfunction.
  • Inosine can be administered in any appropriate way and in any appropriate form, including as a chemical entity per se, for example alone or as part of a product, e.g. a composition or pharmaceutical composition, which contains inosine as an active component.
  • a product e.g. a composition or pharmaceutical composition, which contains inosine as an active component.
  • Some appropriate inosine containing compositions or products are commercially available, e.g. as oral formulations (e.g. capsules) or injectable formulations (e.g. ampoules).
  • inosine can conveniently be provided as a dry powder, e.g. for oral
  • inosine might be encapsulated in capsules or be provided as tablets, e.g. 100 or 500 mg capsules or tablets.
  • the daily dose (e.g. for a human subject) can be any appropriate effective dose, for example can be in a range from 100 mg to 2000 or 3000 mg.
  • Inosine can also be administrated by intravenous or intramuscular injection (or other parenteral routes of administration), for example after reconstitution of a dry form of inosine.
  • inosine might be administered at a dose, e.g. a daily dose, of up to 500 mgs, e.g. up to 100 mgs, 200 mgs, 300 mgs, 400 mgs, or 500 mgs.
  • Such doses can be administered in any appropriate volume, conveniently volumes of up to 10 mis, e.g. in volumes of up to 1 ml, 2 ml, 5 ml or 10 mis or doses of 20 to 100 mg/ml.
  • the inosine may be administered as the sole active component or administered with other active components.
  • any agent capable of stimulating inosine production e.g. in vivo
  • a bacterial strain capable of stimulating inosine production in vivo is used.
  • the present invention thus provides a new method of selecting bacterial strains, in particular strains of lactic acid bacteria, which are useful as probiotics and as pharmaceuticals in therapy.
  • Such strains are selected for their ability to stimulate inosine production, in particular for their ability to stimulate inosine production in vivo upon administration to a subject.
  • the strains for use in the methods of the present invention can stimulate or induce inosine production in any appropriate way.
  • the invention includes embodiments where the bacterial strains themselves are capable of producing inosine directly, e.g. secrete inosine, or embodiments where the bacterial strains stimulate or induce inosine production indirectly.
  • strains for use in the methods of the present invention can also modulate inosine utilization by e.g altering the uptake/excretion, e.g from the GI tract.
  • appropriate strains for use in the present invention are those which can result in an increase in inosine levels in the subject in question.
  • One aspect of the present invention thus provides a method for the selection of a bacterial strain, preferably a lactic acid bacterial strain, capable of stimulating inosine production, wherein said method comprises:
  • a suitable animal model e.g. a mouse model, e.g. a scurfy mouse model
  • samples e.g. plasma and/or stool samples from said animal model, e.g. mouse model;
  • analysis e.g. a non-targeted metabolomic analysis platform
  • step c) can comprise the measurement or analysis of inosine alone or with other metabolites by any appropriate method.
  • Preferred methodology for carrying out one or more of such steps are outlined in the Examples.
  • plasma or other systemic samples, e.g. peripheral blood or serum
  • the present invention provides a method for the selection of a bacterial strain, preferably a lactic acid bacterial strain, by screening a bacterial strain, e.g. a lactic acid bacterial strain, for its ability to stimulate inosine production, and selecting a strain which has that ability.
  • Preferred method steps are outlined above.
  • Bacterial strains with the ability to stimulate high or significant or increased levels of inosine are preferred, for example bacterial strains that stimulate inosine production at a level which is therapeutically effective in a subject.
  • a bacterial strain is selected for its ability to stimulate inosine production in vivo and in preferred embodiments the selection methods are in vivo methods.
  • bacterial strains for use in the invention have the ability to stimulate inosine production in vivo
  • a preferred option is to assess the strains in an appropriate experimental in vivo assay, e.g. using an appropriate mouse or other experimental animal model, e.g. a scurfy mouse model.
  • Appropriate methods of measuring stimulation of inosine production by strains of bacteria and levels of inosine production, e.g. in the plasma, stool or GI tract, would be well known to a person skilled in the art. For example, methods of relative quantification of inosine production in appropriate mouse models and comparing levels produced in wild type mice, disease model mice, and mice to which bacterial strains have been administered, are described in the Examples.
  • the selection method will involve the step of detecting or determining the amount or level (e.g. the concentration, level, or relative level) of inosine stimulation by a candidate bacterial strain, e.g. in comparison to inosine stimulation where no bacterial strain is present.
  • the amount or level e.g. the concentration, level, or relative level
  • other embodiments will involve the further steps of culturing or propagating or producing such bacterial strains and optionally formulating said cultured or propagated or produced strains into a composition comprising said strain, e.g. a pharmaceutical or nutritional composition, e.g. as described elsewhere herein, or possibly storing such bacterial strains for future uses, for example through lyophilisation or freeze drying, after which they may be cultured, etc., and optionally formulated, etc., as described above.
  • the amount of inosine generated can be quantified (e.g. in an absolute or relative manner) and the bacterial strain, e.g. the lactic acid bacterial strain, which stimulates the production of the highest amount or level or concentration of inosine can be selected.
  • any bacterial strains which are capable of stimulating increased (preferably significantly increased) levels of inosine, e.g. in comparison to the levels observed in the absence of said bacterial strain, can be selected.
  • an appropriate bacterial strain has been selected using the method of the present invention it can then be used for stimulating the production, e.g. the local or systemic production (or increase), of inosine in a subject.
  • Said bacterial strains thus also have to be capable of stimulating the production, e.g. the local or systemic production, of inosine in a subject, i.e. in vivo.
  • any of the selection methods of the invention which are carried out in vivo e.g. using an in vivo non-human animal model
  • such methods are experimental methods and are not performed for the purposes of therapy or surgery, e.g. are not practiced as methods of treatment of the human or animal body by surgery or therapy or are non-therapeutic or nonsurgical methods.
  • a further aspect of the invention thus provides the use of a bacterial strain of the invention or a bacterial strain selected, obtained or obtainable by the selection method of the invention, in a method for stimulating the production of inosine, e.g. in vivo.
  • the invention thus provides a method of stimulating the production of inosine in vivo, said method comprising the administration to a subject of a bacterial strain that is capable of stimulating the production of inosine in vivo.
  • the selection methods of the invention can also be used to select new bacterial strains which are suitable for use in therapy as described herein, wherein said strains are capable of stimulating the production of inosine in vivo.
  • the inosine can be provided by use of a bacterial strain.
  • said strain can stimulate the production of inosine (e.g. by an indirect mechanism where the bacterial strain increases inosine levels by some means involving a further component or entity or process other than the strain itself, e.g. by inducing other cells to release inosine or by promoting absorption of inosine such that circulatory levels, e.g. blood/plasma levels, of inosine are increased).
  • circulatory levels e.g. blood/plasma levels
  • said strain can modulate inosine utilization by e.g altering the uptake/excretion, e.g from the GI tract.
  • a further aspect of the present invention provides a bacterial strain, e.g. a lactic acid bacterial strain, selected, obtained or obtainable by the selection method of the invention, wherein said strain is capable of stimulating or inducing the production of inosine, for use in the production, e.g. local or systemic production (or increase), of inosine in a subject.
  • said strains can stimulate or induce production of inosine (or increased levels of inosine) in vivo.
  • Alternative embodiments of the invention provide a bacterial strain, e.g. a lactic acid bacterial strain, wherein said strain is capable of stimulating or inducing the production of inosine, for use in the production, e.g. local or systemic production (or increase), of inosine in a subject.
  • said strains can stimulate or induce production of inosine (or increased levels of inosine) in vivo.
  • this bacterial strain and its uses are described elsewhere herein.
  • preferred diseases to be treated in accordance with such embodiments are described elsewhere herein.
  • preferred uses are in the treatment of diseases which will benefit from inosine production (or increased levels of inosine), for example diseases associated with a deficiency or reduction in inosine or diseases associated with Treg deficiency or Treg dysfunction.
  • Methods of treatment or methods for stimulating the production, e.g. local or systemic production (or increase), of inosine in a subject are also provided, said methods comprising the administration of a bacterial strain, e.g.
  • a lactic acid bacterial strain selected, obtained or obtainable by the selection method of the invention, or the administration of a bacterial strain, e.g. a lactic acid bacterial strain, wherein said strain is capable of stimulating or inducing the production of inosine, to said subject in an amount effective to stimulate production, e.g. local or systemic production, or increased level, of inosine in said subject.
  • a bacterial strain e.g. a lactic acid bacterial strain
  • said strain is capable of stimulating or inducing the production of inosine, to said subject in an amount effective to stimulate production, e.g. local or systemic production, or increased level, of inosine in said subject.
  • preferred features of the strain and its therapeutic uses are described elsewhere herein. For example, preferred diseases to be treated in accordance with such embodiments are described elsewhere herein.
  • a bacterial strain e.g. a lactic acid bacterial strain, selected, obtained or obtainable by the selection method of the invention, wherein said strain is capable of stimulating or inducing the production of inosine, in the manufacture of a composition or medicament for use in the production, e.g. local or systemic production, or increased level, of inosine in a subject.
  • a bacterial strain e.g. a lactic acid bacterial strain
  • said strain is capable of stimulating or inducing the production of inosine, in the manufacture of a composition or medicament for use in the production, e.g. local or systemic production, or increased level, of inosine in a subject.
  • Such uses are therapeutic uses and preferred features of the strain and its therapeutic uses are described elsewhere herein. For example, preferred diseases to be treated in accordance with such embodiments are described elsewhere herein.
  • Products or compositions comprising said bacterial strains and uses of said products or compositions in methods and uses as described herein form yet further aspects of the invention.
  • a bacterial strain e.g. a lactic acid bacterial strain, selected, obtained or obtainable by the selection methods of the invention, wherein said strain is capable of stimulating the production of inosine (e.g. in vivo), is a yet further aspect of the invention.
  • Therapeutic uses of the strains selected by the present invention are also provided. In preferred such embodiments of the invention the strain selected, obtained, obtainable or used is not
  • Lactobacillus reuteri DSM 17938 Lactobacillus reuteri DSM 17938.
  • any appropriate bacterial strain e.g. probiotic bacterial strain, for example any probiotic bacteria
  • any appropriate bacterial strain e.g. probiotic bacterial strain, which is capable of stimulating the production of inosine (or increasing the levels of inosine)
  • any appropriate bacterial strain e.g. probiotic bacterial strain, which is capable of stimulating the production of inosine (or increasing the levels of inosine)
  • Such strains can thus be used for the in vivo production or local or systemic production (or increasing levels) of inosine in a subject.
  • Preferred bacterial strains are lactic acid bacteria, e.g. Lactobacillus. Particularly preferred bacterial strains are Lactobacillus reuteri.
  • a yet further aspect of the invention provides the use of such strains to treat one or more of the diseases as described herein.
  • the strain used is not Lactobacillus reuteri DSM 17938.
  • the Lactobacillus reuteri DSM 17938 strain was deposited under the Budapest Treaty at the DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (Mascheroder Weg lb, D-38124 Braunschweig) on 30 January 2006.
  • Such bacterial strains can be isolated strains or pure cultures. In some embodiments such strains will not correspond to naturally occurring bacterial strains.
  • the inosine or the bacterial strains as described herein, or the strains selected by or obtainable by the selection methods of the invention have uses in therapy.
  • a further aspect of the invention provides inosine or the inosine stimulating strains as described herein, or strains which are selected, obtained or obtainable using the selection methods of the invention, for use in the production, e.g. local or systemic production, of inosine in a subject.
  • said inosine or inosine stimulating strains is used for the treatment of a disease (or condition) which will benefit from production or increased production, e.g. local or systemic production, of inosine.
  • said inosine or inosine stimulating strains is used for the treatment of a disease (or condition) which can be treated with the administration, e.g. local or systemic administration, of inosine.
  • a disease or condition
  • exemplary diseases are those associated with a deficiency or reduction in inosine levels.
  • Production of inosine refers in general to an increase in level (e.g. concentration) or amount of inosine in a subject. Such production can for example be local production and/or systemic production.
  • Local production or local levels of inosine refers to amounts (or levels, e.g. concentration) of inosine at a site where inosine or a bacterial strain as described herein is administered, e.g. the GI tract, GU tract, oral cavity, etc.
  • Systemic production or systemic levels of inosine refers to amounts (or levels, e.g. concentration) of inosine as found in the circulation, in particular in peripheral blood, plasma or serum.
  • an increase in inosine when referred to herein, e.g. as caused by the stimulation of inosine production by a bacterial strain or by the direct administration of inosine or an inosine containing compound or product or composition, such an increase can refer to an increase in amount or level (e.g. concentration) of inosine.
  • concentration e.g. concentration
  • increases are measurable increases, more preferably they are significant increases, preferably clinically significant or statistically significant increases, for example with a probability value of ⁇ 0.05, when compared to an appropriate control level or value (e.g. compared to an untreated or placebo treated sample or subject, e.g. where no inosine is administered, or compared to a sample or subject where the bacterial strain is not present).
  • levels of inosine might be increased by at least 0.5 fold, 1 fold, 2 fold, 3 fold, 4 fold, 5 fold, 10 fold, or more as compared to an appropriate control level or value.
  • the increases are such as to give rise to a therapeutic benefit or effect as described elsewhere herein, e.g. such as to inhibit or reduce the differentiation of TH1 and/or TH2 cells.
  • Such increases in inosine are generally observed in vivo and can for example be local increases and/or systemic increases.
  • Local increase of inosine refers to increased amounts (or levels, e.g. concentration) of inosine at a site where inosine or a bacterial strain as described herein is administered, e.g. the GI tract, GU tract, oral cavity, etc.
  • Systemic increase of inosine refers to increased amounts (or levels, e.g. concentration) of inosine as found in the circulation, in particular in blood, plasma or serum. Increased systemic levels are preferred and the invention provides therapeutic methods based on the systemic administration of inosine or an increase in systemic inosine, e.g. inosine in the blood, plasma or serum.
  • inosine or inosine stimulating bacterial strains as described herein, or bacterial strains which are selected, obtained or obtainable using the selection methods of the invention can be used for the treatment of a disease associated with or characterised by Treg deficiency or a disease associated with or characterised by Treg dysfunction, e.g. Treg deficiency or Treg dysfunction induced (or mediated or associated) inflammatory disease or autoimmune disease.
  • a disease associated with or characterised by Treg deficiency or a disease associated with or characterised by Treg dysfunction e.g. Treg deficiency or Treg dysfunction induced (or mediated or associated) inflammatory disease or autoimmune disease.
  • Exemplary diseases are those associated with or characterised by deficiency or dysfunction in Foxp3 + Tregs.
  • the inventors have shown that inosine can mimic the effect of Tregs on inhibiting or reducing the differentiation of CD4 + cells e.g. TH1/TH2 cells.
  • the present invention can be used to treat any diseases associated with Treg deficiency or Treg dysfunction, as the inosine which is administered or which is stimulated by the bacterial strains can substitute for (or compensate for) the lack of (or the dysfunctional) Tregs or mimic the Tregs which are absent or dysfunctional.
  • the therapeutic methods and uses of the present invention can be used to inhibit or reduce the differentiation of CD4+ T-cells, in particular THl and/or TH2 cells (and for example inhibit or reduce TH1/TH2 cell induced or mediated inflammation or immune response).
  • diseases to be treated are those in which it is desirable to inhibit or reduce the differentiation of CD4+ T-cells, in particular THl and/or TH2 cells, or to inhibit or reduce THl and/or TH2 cell induced or mediated inflammation or immune response.
  • the therapeutic methods and uses of the present invention (or the methods and uses of inosine, including bacterial strains which stimulate inosine production as described herein) can be used to treat autoimmune diseases.
  • CD4+ T-cell driven diseases in particular THl and/or TH2 cell driven diseases, e.g. diseases caused by or associated with abnormal (or aberrant or undesired) function or behaviour of, e.g. unregulated behaviour of, CD4+ T-cells, in particular THl and/or TH2 cells, for example autoimmune diseases or other inflammatory diseases (e.g. diseases associated with abnormal (or aberrant or undesired) or increased inflammation).
  • Other diseases to be treated are those in which CD4+ T-cells, in particular THl and/or TH2 cells, are increased. Such an increase in CD4+ T-cells, e.g.
  • THl and/or TH2 cells observed in such diseases can be for example an increase in absolute numbers or proportions of CD4+ T-cells, e.g. THl and/or TH2 cells, or for example an increase in the levels of the cytokines produced by CD4+ T-cells, e.g. THl and/or TH2 cells.
  • Such increases in CD4+ cells, in particular THl and/or TH2 cells, or increases in cytokines can be observed in the plasma or in other parts of the subject, e.g. the spleen or lymph nodes.
  • An exemplary cytokine which is characteristic of THl cells and can be measured is IFN- ⁇ and an exemplary cytokine which is characteristic of TH2 cells and can be measured is IL-4.
  • Tregs are a subpopulation of T cells which modulate the immune system, maintain tolerance to self-antigens, and abrogate autoimmune disease. Tregs generally suppress or down regulate induction and proliferation of effector T cells. Regulatory T cells come in many forms with the most well-understood being those that express CD4, CD25, and Foxp3 (CD4+CD25+ regulatory T cells). Genetic mutations in the gene encoding Foxp3 have been identified in both humans and mice based on the heritable disease caused by these mutations. Humans with mutations in Foxp3 suffer from a severe and rapidly fatal autoimmune disorder known as Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome.
  • IPEX Enteropathy X-linked
  • IPEX-like syndromes for example due to or associated with mutations in one or more of: CTLA4, CD25, STAT1, STAT5b, ITCH and IL-2Rb.
  • the present invention further provides inosine or inosine stimulating bacterial strains as described herein, or bacterial strains which are selected, obtained or obtainable using the selection methods of the invention, for use in the treatment of a disease or condition as described herein, in particular the treatment of IPEX, a disease associated with a mutation or alteration in Foxp3, or IPEX-like syndromes, for example due to or associated with mutations in one or more of: CTLA4, CD25, STAT1, STAT5b, ITCH and IL-2Rb.
  • disease(s) associated with or “condition(s) associated with” can also refer to “disease(s) (or condition(s)) characterised by” or “disease(s) (or condition(s)) caused by”.
  • inosine including bacterial strains which stimulate inosine production
  • inosine as described herein generally result in the reduction or alleviation of the relevant disease or symptoms of disease, for example can result in an increased or prolonged survival time.
  • Said uses can result in a significant increase in levels of inosine in the subject or a reduced immune response (e.g. reduced inflammation or a reduced immune response mediated by effector T cells such as TH1 and/or TH2 cells) or reduced autoimmunity.
  • the increase in levels of inosine can also compensate for a lack of Treg cells or can mimic Treg cells and can result in a suppressed or reduced immune response, e.g. an inhibition or reduction in differentiation of CD4 + effector cells, in particular THl and/or TH2 cells.
  • This can for example be observed or assessed by any appropriate method which would be well known to a person skilled in the art, for example, by looking for a decrease or reduction in IL-4 (TH2) and/or IFN- ⁇ (THl) levels, e.g.
  • embodiments of the invention involve the provision of increased circulatory inosine levels, e.g. in the blood/plasma of a subject.
  • increased levels can be achieved by administering inosine intravenously or intramuscularly, or, alternatively, by for example inosine being absorbed more efficiently from the GI tract or released from other cells in the blood/plasma as an indirect consequence of the bacteria.
  • Preferred embodiments of the invention involve bacterial strains which can increase or stimulate the absorption of inosine from a site of local administration of bacteria (e.g. GI tract) to blood/plasma.
  • increased inosine levels in blood/plasma or increased systemic levels of inosine
  • Such reduction or alleviation of disease or symptoms thereof e.g. clinical symptoms or severity, e.g. effects on survival
  • any appropriate assay for the disease or symptom or parameter e.g. levels of cytokines or types of T-cells or survival
  • the reduction or alleviation of disease or symptoms is measurable, and preferably significant, e.g. clinically significant or statistically significant, preferably with a probability value of ⁇ 0.05.
  • Such reduction or alleviation of disease or symptoms are generally determined compared to an appropriate control individual or population, for example a healthy animal or subject (or a population thereof) or an untreated or placebo treated animal or subject (or a population thereof), or, conveniently, the same individual subject before treatment.
  • inosine including bacterial strains which stimulate inosine production
  • administration of the inosine as described herein in the methods of treatment and uses of the invention is carried out in pharmaceutically or physiologically effective amounts, to subjects (animals or mammals) in need of treatment.
  • said methods and uses may involve the additional step of identifying a subject in need of treatment.
  • Treatment of disease or conditions in accordance with the present invention includes cure of said disease or conditions, or any reduction or alleviation of disease (e.g. reduction in disease severity) or symptoms of disease.
  • the methods and uses of the prevent invention are suitable for prevention of diseases or conditions as well as active treatment of diseases or conditions (for example treatment of preexisting disease).
  • prophylactic treatment is also encompassed by the invention.
  • treatment or therapy also includes prophylaxis or prevention where appropriate.
  • Such preventative (or protective) aspects can conveniently be carried out on healthy or normal or at risk subjects and can include both complete prevention and significant prevention.
  • significant prevention can include the scenario where severity of disease or symptoms of disease is reduced (e.g. measurably or significantly reduced) compared to the severity or symptoms which would be expected if no treatment is given.
  • a yet further aspect of the invention provides inosine (including bacterial strains which stimulate inosine production) for the therapeutic uses as defined elsewhere herein, wherein said use further comprises the administration of at least one further agent, e.g. a therapeutic or nutritional agent.
  • exemplary agents might be substrate components or other components which will increase or enhance the stimulation of the production of inosine by said bacterial strain, or a source of such components.
  • a carbon source to support the metabolic activity of the bacteria can also be added to the final formulation.
  • Said further agents can be administered together with the bacterial strains (e.g. as a combined preparation or a single composition) or can be administered separately. If administered separately, said further agents can be administered at the same time (or substantially the same time) as the bacterial strains, or at different time points. Suitable administration regimes and timings can readily be determined by the skilled person depending on the further agent in question.
  • the present invention also provides a composition comprising:
  • a bacterial strain e.g. a lactic acid bacterial strain, capable of stimulating the
  • inosine e.g. a lactic acid bacterial strain, selected, obtained or obtainable by the selection method of the invention.
  • subject includes any mammal, for example humans and any livestock, domestic or laboratory animal. Specific examples include mice, rats, pigs, cats, dogs, sheep, rabbits, cows, horses and monkeys. Preferably, however, the subject is a human subject. In embodiments relating to therapeutic methods and uses described herein, appropriate subjects are those having, suspected of having, or at risk of having the disease to be treated.
  • the methods and uses of the invention generally involve the administration of the inosine or the selected bacterial strain as defined herein, e.g. a lactic acid bacterial strain, to a subject, preferably a human.
  • administration is a form of local administration, e.g. oral, rectal, vaginal, topical or by tube-feeding.
  • the inosine or bacterial strains as described herein can be administered to the GI tract, GU tract or oral cavity, as desired or appropriate.
  • intravenous or intramuscular injection will be appropriate.
  • An appropriate mode of administration and formulation of the inosine or bacterial strains, etc. is chosen depending on the site where inosine or stimulation of inosine production, e.g. local production or systemic production, or increased production or increased levels of inosine, is desired.
  • a preferred mode of administration is oral in order to e.g. facilitate or result in increased inosine levels in the gastrointestinal tract.
  • such a mode of administration can also result in an increase in inosine levels in the blood/plasma and this is preferred in some embodiments.
  • inosine e.g. an inosine containing product or composition
  • intravenous or intramuscular injection can be appropriate.
  • inosine including bacterial strains which stimulate inosine production
  • a dosage and administration regime is generally chosen such that the inosine or bacterial strains
  • inosine levels or the stimulation of inosine production e.g. local production or systemic production, or an increased production or increased levels of inosine, e.g. increased local production or systemic production, and to give rise to the desired therapeutic effects or health benefits (for example an increase in Tregs (or an increase in functional Tregs) or a compensation for lack of Tregs or Treg deficiency as described elsewhere herein, e.g. an inhibition or reduction in the differentiation of TH1 and/or TH2 cells, or an inhibition or reduction in autoimmunity, e.g. autoimmunity associated with Treg deficiency or dysfunction, or other reduced TH1 and/or TH2 cell mediated inflammation, or any other reduction or alleviation of the relevant disease or symptoms of disease for example as described elsewhere herein).
  • inosine levels or the stimulation of inosine production e.g. local production or systemic production
  • an increased production or increased levels of inosine e.g. increased local production or system
  • inosine is prepared as a dry powder, e.g. for oral administration.
  • inosine might be encapsulated in capsules, e.g.
  • 100 or 500 mg capsules and the daily dose can be in a range from.
  • Inosine can also be administrated by intravenous or
  • inosine might be administered at a dose, e.g. a daily dose, of up to 500 mgs, e.g. up to 100 mgs, 200 mgs, 300 mgs, 400 mgs, or 500 mgs.
  • a dose e.g. a daily dose
  • Such doses can be administered in any appropriate volume, conveniently volumes of up to 10 mis, e.g. in volumes of up to 1 ml, 2 ml, 5 ml or 10 mis or doses of 20 to 100 mg/ml.
  • said dosage is a therapeutically effective dosage which is appropriate for the type of animal and condition being treated.
  • daily doses of 10 4 to 10 13 for example 10 5 to 10 9 , or 10 6 to 10 8 , or 10 8 to 10 10 , or 10 9 to 10 12 total CFUs of
  • a preferred daily dose is around 10 total CFUs, e.g. 10 to 10 or 10 to 10 9 .
  • Another preferred daily dose is around 10 12 total CFUs, e.g. 10 10 or 10 11 to 10 13 , or 10 n to 10 12 or 10 12 to 10 13 .
  • Inosine as used herein is given its art understood meaning. It is a nucleoside that is formed when hypoxanthine is attached to a ribose ring and can be manufactured by methods which are well known and described in the art, e.g. by fermentation.
  • the systematic (IUPAC) name for inosine is 9-[2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6,9-dihydro- 3H-purin-6-one.
  • Inosine preparations for use in the present invention can be readily obtained, for example, inosine has been used in other pharmaceutical applications and inosine is commercially available as a dietary or nutritional supplement.
  • the inosine for use as described herein can be in the form of a product or composition containing inosine or a salt thereof, e.g. a pharmaceutically acceptable salt thereof, examples of which would be well known to those skilled in the art.
  • the inosine can be in the form of a composition (e.g. a pharmaceutical composition) comprising said inosine compound, together with one or more acceptable (e.g. pharmaceutically acceptable) carriers, excipients or diluents.
  • acceptable carriers, excipients and diluents are well known in the art and can be selected with regard to the intended route of
  • binders examples include binders, lubricants, suspending agents, solvents, coating agents, solubilising agents, preserving agents, wetting agents, emulsifiers, surfactants, sweeteners, colourants, flavouring agents, odorants, buffers, antioxidants, stabilising agents and/or salts.
  • Inosine containing compositions are well known and described in the art and any of these may be used.
  • the inosine compounds described herein may be formulated with one or more conventional carriers and/or excipients according to techniques well known in the art.
  • these may be formulated in conventional oral administration forms, e.g. tablets, coated tablets, capsules, powders, granulates, solutions, dispersions, suspensions, syrups, emulsions, etc. using conventional excipients, e.g. solvents, diluents, binders, sweeteners, aromas, pH modifiers, viscosity modifiers, antioxidants, etc.
  • Suitable excipients may include, for example, corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, ethanol, glycerol, sorbitol, polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fats or suitable mixtures thereof, etc. It is envisaged that the inosine compounds or compositions described herein can also be administered by other conventional administration routes, e.g. parenterally. Where parenteral administration is employed this may, for example, be by means of intravenous, subcutaneous or intramuscular injection.
  • Treg refers to regulatory T cells. Regulatory T cells (Tregs) play a critical role in maintaining the balance between immune activation and tolerance and thus in controlling the immune response and inflammation. Tregs are a suppressive subset of CD4 + T helper cells and are important for the immune response regulation. Tregs are thus
  • T- regs are a different subset of CD4+ T cells to TH1 and TH2 cells. A person skilled in the art would readily be able to distinguish between these sub-types, e.g. through the use of characteristic cell surface markers. For example, Tregs can be distinguished from other subtypes of T-cells as they are positive for FOXP3 in addition to CD4.
  • Treg-dysfunction means that the regulatory T cells (Tregs) do not function properly (or function abnormally or aberrantly or in an undesired or pathological way) for example by loosing their control of the immune response, e.g. resulting in an uncontrolled immune response or immune activity. It includes an imbalance between Tregs and T effector cells, e.g. in which the T effector cells (e.g. TH1 and/or TH2 cells) are over reactive or over produced, e.g. resulting in an uncontrolled or increased immune response or inflammation (e.g. TH1 and/or TH2 cell mediated or induced inflammation).
  • Treg-dysfunction can be a result of abnormal or aberrant or pathological FOXP3 function, for example caused by a mutation, alteration or other defect in FOXP3, e.g. the FOXP3 gene or protein).
  • Treg-deficiency means a lack of regulatory T cells (Tregs) and includes a reduction in numbers of Tregs from normal levels or a situation where not enough Tregs are produced.
  • Treg deficiency results in the development of a disease called immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) which is a severe autoimmune disease that starts early in infants.
  • Treg deficiency or dysfunction can be analyzed in animal models such as SF (scurfy) mice which have a deletion in the forkhead domain of Foxp3 and fail to develop thymic-derived Foxp3+ regulatory T cells (nTreg). This results in the development of a fatal
  • a bacterial strain that can stimulate the production of inosine can result in prolonged survival and other beneficial effects in SF mice, thereby apparently compensating for Treg deficiency/dys function in such mice.
  • Appropriate controls would readily be identified by a person skilled in the art and might include non- treated subjects or a level of a particular parameter in the same individual subject measured at an earlier time point (e.g. comparison with a "baseline” level in that subject).
  • the decrease or reduction will be significant, for example clinically or statistically significant.
  • the term “increase” or “enhance” (or equivalent terms) as described herein, e.g. in relation to levels of survival, cytokines, THl cells, TH2 cells or Tregs, includes any measurable increase or elevation when compared with an appropriate control.
  • Appropriate controls would readily be identified by a person skilled in the art and might include non-treated subjects or a level of a particular parameter in the same individual subject measured at an earlier time point (e.g. comparison with a "baseline” level in that subject).
  • the increase will be significant, for example clinically or statistically significant.
  • Wild-type C57BL/6 and heterozygous B6.Cg-Foxp3sf/J female mice were purchased from Jackson Laboratories. All mice were then bred and housed at The University of Texas Health Science Center at Houston, Houston, Texas, USA under institutionally-approved protocols (Institutional Animal Care and Use Committee no. AWC-14-056). Heterozygous B6.Cg- Foxp3sf/J female mice were bred to C57BL/6J male mice to generate hemizygous B6.Cg- Foxp3sf/Y, scurfy (SF) male mice. Because the Foxp3 gene is on the X chromosome, in each litter of breeding pairs, all males are either SF used as the experiments or WT littermates as the controls. Animal numbers used in each group of different experiments are indicated in the Figures and Figure Legends.
  • L. reuteri Human breast milk-derived Lactobacillus reuteri DSM17938 (L. reuteri) was provided by Biogaia AB (Stockholm, Sweden). L. reuteri was prepared as described previously (Liu Y. et al. Am. J. Physiol Gastrointest. Liver Physiol 307, G177-G186 (2014)). SF mice were given L. reuteri by gavage, daily, starting from 8 days of life (d8) (L. reuteri early treatment) or dl5 (L. reuteri late treatment), until the end of the experimental procedure, as indicated in the Fig. la and b, respectively. Each mouse was given 10 7 CFU of L. reuteri per day.
  • Inosine (Sigma- Aldrich) was dissolved in sterilized water at 40 mg/ml. For determining the effect of inosine on autoimmunity in SF mice, 800mg/kg of inosine per day was orally administered to SF mice from d8 until the end of the experiment, as indicated in Fig. lc.
  • MACS buffer consisting of phosphate buffered saline (PBS), 0.5% bovine serum albumin (BSA) (Hyclone Laboratories) and 2 mM EDTA (Lonza).
  • PBS phosphate buffered saline
  • BSA bovine serum albumin
  • Na ' ive CD4+ T cells were isolated from the spleens of 6-8-week-old C57BL/6 or adenosine receptor knockout mice by magnetic cell sorting, using a na ' ive CD4+ T cell isolation kit (MACS Miltenyi Biotec).
  • na ' ive T cells (5 x lO 5 cells/well) were plated in 24-well plates containing 1 ⁇ g/mL anti-CD3, 2 ⁇ g/mL anti-CD28, 20 ng/mL IL-2, 10 ⁇ g/mL anti-IL-4 neutralizing antibody, and 20 ng/mL recombinant mouse IL-12 in RPMI1640 complete medium at 37°C for 5 days with or without 2 mM of inosine.
  • na ' ive T cells were cultured in the presence of 1 ⁇ g/mL anti-CD3, 2 ⁇ g/mL anti-CD28, 20 ng/mL 11-2, 10 ⁇ g/mL anti-IFN- ⁇ neutralizing antibody and 10 ng/mL recombinant mouse IL-4 in RPMI1640 complete medium at 37°C for 5 days with or without 2 mM of inosine. At day 5, the cells were stimulated with PMA and inomycin in the presence of brefeldin A, as mentioned above.
  • na ' ive CD4+ T cells For evaluation of the purity of na ' ive CD4+ T cells, after sorting, cells were stained using fiuorescein-labeled CD44, CD45RB, CD4, and CD62L.
  • TH1 and TH2 cells were surface-stained by fluorescein-labeled- CD4 and intracellularly stained with IFN- ⁇ for TH1 and IL-4 for TH2. Intracellular staining was performed with a fixation/permeabilization kit, according to the manufacturer's protocol (eBioscience, San Diego, CA).
  • Splenic lymphocytes were split into 96-well plates at an initial density of 2 x 10 4 cells per well and were incubated with different doses of inosine under control, 40 ⁇ / ⁇ 1 of LPS or 10 ⁇ / ⁇ 1 of PHA condition, respectively. After 96 h, cell viability was measured by TACS XTT cell proliferation assay kit (Trevigen, Inc. Gaithersburg, MD).
  • Plasma cytokine levels of IFN- ⁇ , IL-4, IL-2, IL-1 ⁇ and IL-10 were assessed using a mouse multi-spot proinflammatory panel kit from Meso Scale Discovery (Gaithersburg, MD), according to the manufacturer's protocol.
  • Feces expressed from cecum to rectum were collected from groups of WT, SF and SF with L. reuteri treatment (SFL) at the indicated age (Fig. la-b).
  • Stool DNA was extracted by using Quick Stool DNA Isolation Kit (Qiagen).
  • the composition of the stool microbiota was analyzed using high-throughput sequencing analysis of PCR-amp lifted 16s rRNA genes as previous described (Gupta,R.W. et al. J. Pediatr. Gastroenterol. Nutr. 56, 397-400 (2013)). Bacterial diversity, species composition and abundance were assessed using QIIME
  • Plasma and stool metabolites were measured by Metabolon Inc as previous described (He B. et al. Sci. Rep. 5, 10604 (2015)). A total of 657 metabolites in stool and 525 metabolites in plasma were detected by a non-targeted metabolomic analysis platform including UPLC- MS/MS and GC/MS, respectively. The metabolomic data were then analyzed by pattern recognition analyses (unsupervised principal component analysis and Heat-map), revealing the biochemical perturbations induced by Treg-deficiency or L. reuteri treatment.
  • L. reuteri (Fig. 2d- f and Fig. 3d, e). L. reuteri also rescued the effects of Treg-deficiency on villus height and crypt depth in the small intestine (Fig. 4a-c). The histopathology, cytokine measurements and lymphocyte investigation were done as described above. These results show that L. reuteri may treat, as well as prevent, autoimmunity in SF mice, and also that L. reuteri can be used in the treatment of a T-reg deficient disease such as IPEX in humans. EXAMPLE 2
  • the level of inosine in feces was not changed by Treg-deficiency but was reduced by L. reuteri treatment (Fig. 6).
  • the reduced inosine in feces might be related to the increased absorption in the small intestine, due to improvement of villus height, crypt depth in the intestine.
  • Other metabolites involved in inosine metabolism were unchanged in feces of SFL mice (Fig. 7b).
  • inosine can be used in the treatment of a T-reg deficient disease such as IPEX in humans.

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Abstract

La présente invention concerne l'utilisation de l'inosine dans le traitement d'une maladie associée à une déficience en Treg ou à un dysfonctionnement des Treg, en particulier une dérégulation immunitaire, une polyendocrinopathie, une entéropathie, un syndrome lié au chromosome X (IPEX). Selon un mode de réalisation de l'invention, l'inosine peut se présenter sous la forme d'une souche bactérienne qui est capable de stimuler la production d'inosine. La présente invention porte également sur des procédés permettant de stimuler la production d'inosine chez un sujet à l'aide desdites souches, ainsi que sur des procédés permettant la sélection d'une souche bactérienne capable de stimuler la production d'inosine chez un sujet.
PCT/EP2017/062800 2016-05-27 2017-05-26 Utilisation de l'inosine pour le traitement de la déficience en lymphocytes t régulateurs (t-reg) WO2017203048A1 (fr)

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